Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

Fiber and whole grain intakes in relation to liver cancer risk: An analysis in 2 prospective cohorts and systematic review and meta-analysis of prospective studies.

BACKGROUND AND AIMS: The association between fiber or whole grain intakes and the risk of liver cancer remains unclear. We assessed the associations between fiber or whole grain intakes and liver cancer risk among 2 prospective studies, and systematically reviewed and meta-analyzed these results with published prospective studies. APPROACH AND RESULTS: A total of 111,396 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and 26,085 men from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study were included. Intakes of total fiber and whole grains were estimated from validated food frequency questionnaires. Study-specific HRs and 95% CI with liver cancer risk were estimated using multivariable-adjusted Cox regression. We systematically reviewed existing literature, and studies were combined in a dose-response meta-analysis. A total of 277 (median follow-up = 15.6 y) and 165 (median follow-up = 16.0 y) cases of liver cancer were observed in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, respectively. Dietary fiber was inversely associated with liver cancer risk in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (HR 10g/day : 0.69; 95% CI: 0.55-0.86). No significant associations were observed between whole grain intakes and liver cancer risk in either study. Our meta-analysis included 2383 incident liver cancer cases (7 prospective cohorts) for fiber intake and 1523 cases (5 prospective cohorts) for whole grain intake; combined HRs for liver cancer risk were 0.83 (0.76-0.91) per 10 g/day of fiber and 0.92 (0.85-0.99) per 16 g/day (1 serving) of whole grains. CONCLUSIONS: Dietary fiber and whole grains were inversely associated with liver cancer risk. Further research exploring potential mechanisms and different fiber types is needed.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Identification of pre-diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis: A nested case-control study within the ATBC cohort.

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR) <0.05. A chemical set enrichment analysis (ChemRICH) and co-regulatory set analysis suggested that 22/28 lipid classes and 47/83 correlation modules were significantly associated with liver cancer risk (FDR <0.05). Strong positive associations were observed for monounsaturated fatty acids (MUFA), triacylglycerols (TAGs) and phosphatidylcholines (PCs) having MUFA acyl chains. Negative associations were observed for sphingolipids (ceramides and sphingomyelins), lysophosphatidylcholines, cholesterol esters and polyunsaturated fatty acids (PUFA) containing TAGs and PCs. Stearoyl-CoA desaturase enzyme 1 (SCD1), a rate limiting enzyme in fatty acid metabolism and ceramidases seems to be critical in this reprogramming. In conclusion, our study reports pre-diagnostic lipid changes that provide novel insights into hepatic lipid metabolism reprogramming may contribute to a pro-cell growth and anti-apoptotic tissue environment and, in turn, support liver cancer initiation.

Sex-specific associations between sodium and potassium intake and overall and cause-specific mortality: a large prospective U.S. cohort study, systematic review, and updated meta-analysis of cohort studies.

BACKGROUND: The impact of sodium intake on cardiovascular disease (CVD) health and mortality has been studied for decades, including the well-established association with blood pressure. However, non-linear patterns, dose-response associations, and sex differences in the relationship between sodium and potassium intakes and overall and cause-specific mortality remain to be elucidated and a comprehensive examination is lacking. Our study objective was to determine whether intake of sodium and potassium and the sodium-potassium ratio are associated with overall and cause-specific mortality in men and women. METHODS: We conducted a prospective analysis of 237,036 men and 179,068 women in the National Institutes of Health-AARP Diet and Health Study. Multivariable-adjusted Cox proportional hazard regression models were utilized to calculate hazard ratios. A systematic review and meta-analysis of cohort studies was also conducted. RESULTS: During 6,009,748 person-years of follow-up, there were 77,614 deaths, 49,297 among men and 28,317 among women. Adjusting for other risk factors, we found a significant positive association between higher sodium intake (≥ 2,000 mg/d) and increased overall and CVD mortality (overall mortality, fifth versus lowest quintile, men and women HRs = 1.06 and 1.10, Pnonlinearity < 0.0001; CVD mortality, fifth versus lowest quintile, HRs = 1.07 and 1.21, Pnonlinearity = 0.0002 and 0.01). Higher potassium intake and a lower sodium-potassium ratio were associated with a reduced mortality, with women showing stronger associations (overall mortality, fifth versus lowest quintile, HRs for potassium = 0.96 and 0.82, and HRs for the sodium-potassium ratio = 1.09 and 1.23, for men and women, respectively; Pnonlinearity < 0.05 and both P for interaction ≤ 0.0006). The overall mortality associations with intake of sodium, potassium and the sodium-potassium ratio were generally similar across population risk factor subgroups with the exception that the inverse potassium-mortality association was stronger in men with lower body mass index or fruit consumption (Pinteraction < 0.0004). The updated meta-analysis of cohort studies based on 42 risk estimates, 2,085,904 participants, and 80,085 CVD events yielded very similar results (highest versus lowest sodium categories, pooled relative risk for CVD events = 1.13, 95% CI: 1.06-1.20; Pnonlinearity < 0.001). CONCLUSIONS: Our study demonstrates significant positive associations between daily sodium intake (within the range of sodium intake between 2,000 and 7,500 mg/d), the sodium-potassium ratio, and risk of CVD and overall mortality, with women having stronger sodium-potassium ratio-mortality associations than men, and with the meta-analysis providing compelling support for the CVD associations. These data may suggest decreasing sodium intake and increasing potassium intake as means to improve health and longevity, and our data pointing to a sex difference in the potassium-mortality and sodium-potassium ratio-mortality relationships provide additional evidence relevant to current dietary guidelines for the general adult population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Identifier: CRD42022331618.

Helicobacter hepaticus and Helicobacter bilis in liver and biliary cancers from ATBC and PLCO.

BACKGROUND: Helicobacter species (spp.) have been detected in human bile and hepatobiliary tissue Helicobacter spp. promote gallstone formation and hepatobiliary tumors in laboratory studies, though it remains unclear whether Helicobacter spp. contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to Helicobacter (H.) hepaticus or H. bilis proteins was associated with the development of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, and US-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). METHODS: We included 62 biliary and 121 liver cancers, and 190 age-matched controls from ATBC and 74 biliary and 105 liver cancers, and 364 age- and sex-matched controls from PLCO. Seropositivity to 14 H. hepaticus and H. bilis antigens was measured using a multiplex assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for major hepatobiliary cancer risk factors and Helicobacter pylori serostatus. RESULTS: Seropositivity to the H. bilis antigen, P167D, was associated with more than a twofold higher risk of liver cancer (OR: 2.38; 95% CI: 1.06, 5.36) and seropositivity to the H. hepaticus antigens HH0407 or HH1201, or H. bilis antigen, HRAG 01470 were associated with higher risk of biliary cancer (OR: 5.01; 95% CI: 1.53, 16.40; OR: 2.40; 95% CI: 1.00, 5.76; OR: 3.27; 95% CI: 1.14, 9.34, respectively) within PLCO. No associations for any of the H. hepaticus or H. bilis antigens were noted for liver or biliary cancers within ATBC. CONCLUSIONS: Further investigations in cohort studies should examine the role of Helicobacter spp. in the etiology of liver and biliary cancers.

Untargeted metabolomic profiling identifies serum metabolites associated with type 2 diabetes in a cross-sectional study of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

Type 2 diabetes (T2D) is a complex chronic disease with substantial phenotypic heterogeneity affecting millions of individuals. Yet, its relevant metabolites and etiological pathways are not fully understood. The aim of this study is to assess a broad spectrum of metabolites related to T2D in a large population-based cohort. We conducted a metabolomic analysis of 4,281 male participants within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The serum metabolomic analysis was performed using an LC-MS/GC-MS platform. Associations between 1,413 metabolites and T2D were examined using linear regression, controlling for important baseline risk factors. Standardized ß-coefficients and standard errors (SEs) were computed to estimate the difference in metabolite concentrations. We identified 74 metabolites that were significantly associated with T2D based on the Bonferroni-corrected threshold (P < 3.5 × 10-5). The strongest signals associated with T2D were of carbohydrates origin, including glucose, 1,5-anhydroglucitol (1,5-AG), and mannose (ß = 0.34, -0.91, and 0.41, respectively; all P < 10-75). We found several chemical class pathways that were significantly associated with T2D, including carbohydrates (P = 1.3 × 10-11), amino acids (P = 2.7 × 10-6), energy (P = 1.5 × 10-4), and xenobiotics (P = 1.2 × 10-3). The strongest subpathway associations were seen for fructose-mannose-galactose metabolism, glycolysis-gluconeogenesis-pyruvate metabolism, fatty acid metabolism (acyl choline), and leucine-isoleucine-valine metabolism (all P < 10-8). Our findings identified various metabolites and candidate chemical class pathways that can be characterized by glycolysis and gluconeogenesis metabolism, fructose-mannose-galactose metabolism, branched-chain amino acids, diacylglycerol, acyl cholines, fatty acid oxidation, and mitochondrial dysfunction.NEW & NOTEWORTHY These metabolomic patterns may provide new additional evidence and potential insights relevant to the molecular basis of insulin resistance and the etiology of T2D.

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.

Enterohepatic Shunt-Driven Cholemia Predisposes to Liver Cancer.

BACKGROUND & AIMS: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed. METHODS: We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case-control cohort. RESULTS: HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC. CONCLUSIONS: PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber-enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.

Dietary Quality and Circulating Lipidomic Profiles in 2 Cohorts of Middle-Aged and Older Male Finnish Smokers and American Populations.

BACKGROUND: Higher dietary quality is associated with lower disease risks and has not been examined extensively with lipidomic profiles. OBJECTIVES: Our goal was to examine associations of the Healthy Eating Index (HEI)-2015, Alternate HEI-2010 (AHEI-2010), and alternate Mediterranean Diet Index (aMED) diet quality indices with serum lipidomic profiles. METHODS: We conducted a cross-sectional analysis of HEI-2015, AHEI-2010, and aMED with lipidomic profiles from 2 nested case-control studies within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 627) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 711). We used multivariable linear regression to determine associations of the indices, derived from baseline food-frequency questionnaires (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: 1993-2001, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: 1985-1988) with serum concentrations of 904 lipid species and 252 fatty acids (FAs) across 15 lipid classes and 28 total FAs, within each cohort and meta-analyzed results using fixed-effect models for lipids significant at Bonferroni-corrected threshold in common in both cohorts. RESULTS: Adherence to HEI-2015, AHEI-2010, or aMED was associated positively with 31, 41, and 54 lipid species and 8, 6, and 10 class-specific FAs and inversely with 2, 8, and 34 lipid species and 1, 3, and 5 class-specific FAs, respectively. Twenty-five lipid species and 5 class-specific FAs were common to all indices, predominantly triacylglycerols, FA22:6 [docosahexaenoic acid (DHA)]-containing species, and DHA. All indices were positively associated with total FA22:6. AHEI-2010 and aMED were inversely associated with total FA18:1 (oleic acid) and total FA17:0 (margaric acid), respectively. The identified lipids were most associated with components of seafood and plant proteins and unsaturated:saturated fat ratio in HEI-2015; eicosapentaenoic acid plus DHA in AHEI-2010; and fish and monounsaturated:saturated fat ratio in aMED. CONCLUSIONS: Adherence to HEI-2015, AHEI-2010, and aMED is associated with serum lipidomic profiles, mostly triacylglycerols or FA22:6-containing species, which are related to seafood and plant proteins, eicosapentaenoic acid-DHA, fish, or fat ratio index components.

Circulating hormones and risk of gastric cancer by subsite in three cohort studies.

BACKGROUND: Obesity has been positively associated with gastric cancer. Excess fat impacts hormones, which have been implicated in carcinogenesis. We investigated obesity-related hormones and cardia gastric cancer (CGC) and non-cardia gastric cancer (NCGC) risk. METHODS: Nested case-control studies were conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (61 CGCs, and 172 NCGCs and matched controls) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study (100 CGCs and 65 NCGCs and matched controls); serum hormones were measured. In UK-Biobank (n = 458,713), we included 137 CGCs and 92 NCGCs. Sex-specific analyses were conducted. For EPIC and ATBC, odds ratios (ORs), and for UK-Biobank hazard ratios (HRs), were estimated using conditional logistic regression and Cox regression, respectively. RESULTS: Insulin-like growth-factor-1 was positively associated with CGC and NCGC in EPIC men (ORper 1-SD increase 1.94, 95% CI 1.03-3.63; ORper 1-SD increase 1.63, 95% CI 1.05-2.53, respectively), with similar findings for CGC in UK-Biobank women (HRper 1-SD increase 1.76, 95% CI 1.08-2.88). Leptin in EPIC men and C-peptide in EPIC women were positively associated with NCGC (ORT3 vs. T1 2.72, 95% CI 1.01-7.34 and ORper 1-SD increase 2.17, 95% CI 1.19-3.97, respectively). Sex hormone-binding globulin was positively associated with CGC in UK-Biobank men (HRper 1-SD increase 1.29, 95% CI 1.02-1.64). Conversely, ghrelin was inversely associated with NCGC among EPIC and ATBC men (ORper 1-SD increase 0.53, 95% CI 0.34-0.84; ORper 1-SD increase 0.22, 95% CI 0.10-0.50, respectively). In addition, dehydroepiandrosterone was inversely associated with CGC in EPIC and ATBC men combined. CONCLUSIONS: Some obesity-related hormones influence CGC and NCGC risk.

Lipidomics and pancreatic cancer risk in two prospective studies.

Pancreatic ductal carcinoma (PDAC) is highly fatal with limited understanding of mechanisms underlying its carcinogenesis. We comprehensively investigated whether lipidomic measures were associated with PDAC in two prospective studies. We measured 904 lipid species and 252 fatty acids across 15 lipid classes in pre-diagnostic serum (up to 24 years) in a PDAC nested-case control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, NCT00002540) with 332 matched case-control sets including 272 having serial blood samples and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC, NCT00342992) with 374 matched case-control sets. Controls were matched to cases by cohort, age, sex, race, and date at blood draw. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) per one-standard deviation increase in log-lipid concentrations within each cohort, and combined ORs using fixed-effects meta-analyses. Forty-three lipid species were associated with PDAC (false discovery rate, FDR ≤ 0.10), including lysophosphatidylcholines (LPC, n = 2), phosphatidylethanolamines (PE, n = 17), triacylglycerols (n = 13), phosphatidylcholines (PC, n = 3), diacylglycerols (n = 4), monoacylglycerols (MAG, n = 2), cholesteryl esters (CE, n = 1), and sphingomyelins (n = 1). LPC(18:2) and PE(O-16:0/18:2) showed significant inverse associations with PDAC at the Bonferroni threshold (P value < 5.5 × 10-5). The fatty acids LPC[18:2], LPC[16:0], PC[15:0], MAG[18:1] and CE[22:0] were significantly associated with PDAC (FDR < 0.10). Similar associations were observed in both cohorts. There was no significant association for the differences between PLCO serial lipidomic measures or heterogeneity by follow-up time overall. Results support that the pre-diagnostic serum lipidome, including 43 lipid species from 8 lipid classes and 5 fatty acids, is associated with PDAC.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Hair dye use and prostate cancer risk: A prospective analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort.

BACKGROUND: According to the International Agency for Research on Cancer, some hair dye chemicals are considered mutagenic and carcinogenic in humans. One hospital-based study reported a positive association between hair dye use and prostate cancer risk, but no prospective analyses have been conducted. METHODS: This study investigated the association between hair dye use and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort, a large, well-characterized cohort of 29,133 male Finnish smokers. Participants completed questionnaires regarding lifestyle, medical, and risk factor information, including the use of hair dye, which was available for 98.8% of the cohort (28,795 men). Prostate cancer cases were identified through linkage with the Finnish Cancer Registry and the Finnish Mortality Register. Hazard ratios (HRs) and confidence intervals (CIs) were estimated via multivariable Cox proportional hazards regression. RESULTS: During a 28-year period of observation, 2703 incident prostate cancer cases were diagnosed. As reported at the baseline, 75 men used hair dye, and 13 of these men were subsequently diagnosed with prostate cancer. After adjustments for potential confounders, men who used hair dyes experienced substantially higher prostate cancer risk than men who did not (HR, 1.77; 95% CI, 1.03-3.05). CONCLUSIONS: This first prospective investigation of hair dye use and prostate cancer suggests that personal hair dye use may be related to increased risk. The findings warrant re-examination in other prospective cohorts along with studies evaluating specific hair dyes and possible underlying biological mechanisms.

Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men.

BACKGROUND: Abnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships. METHODS: We examined the serum metabolome in relation to prostate cancer survival in a cohort of 1812 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Using an ultrahigh-performance LC-MS/MS platform, we identified 961 known metabolites in prospectively collected serum. Median survival time from diagnosis to prostate cancer-specific death (N=472) was 6.6 years (interquartile range=2.9-11.1 years). Cox proportional hazards regression models estimated hazard ratios and 95% confidence intervals of the associations between the serum metabolites (in quartiles) and prostate cancer death, adjusted for age at baseline and diagnosis, disease stage, and Gleason sum. In order to calculate risk scores, we first randomly divided the metabolomic data into a discovery set (70%) and validated in a replication set (30%). RESULTS: Overall, 49 metabolites were associated with prostate cancer survival after Bonferroni correction. Notably, higher levels of the phospholipid choline, amino acid glutamate, long-chain polyunsaturated fatty acid (n6) arachidonate (20:4n6), and glutamyl amino acids gamma-glutamylglutamate, gamma-glutamylglycine, and gamma-glutamylleucine were associated with increased risk of prostate cancer-specific mortality (fourth versus first quartile HRs=2.07-2.14; P-values <5.2×10-5). By contrast, the ascorbate/aldarate metabolite oxalate, xenobiotics S-carboxymethyl-L-cysteine, fibrinogen cleavage peptides ADpSGEGDFXAEGGGVR and fibrinopeptide B (1-12) were related to reduced disease-specific mortality (fourth versus first quartile HRs=0.82-0.84; P-value <5.2×10-5). Further adjustment for years from blood collection to cancer diagnosis, body mass index, smoking intensity and duration, and serum total and high-density lipoprotein cholesterol did not alter the results. Participants with a higher metabolic score based on the discovery set had an elevated risk of prostate cancer-specific mortality in the replication set (fourth versus first quartile, HR=3.9, P-value for trend<0.0001). CONCLUSIONS: The metabolic traits identified in this study, including for choline, glutamate, arachidonate, gamma-glutamyl amino acids, fibrinopeptides, and endocannabinoid and redox pathways and their composite risk score, corroborate our previous analysis of fatal prostate cancer and provide novel insights and potential leads regarding the molecular basis of prostate cancer progression and mortality.

Multivitamin Use and Overall and Site-Specific Cancer Risks in the National Institutes of Health-AARP Diet and Health Study.

BACKGROUND: Multivitamins are among the most commonly used supplements in the United States, but their effectiveness in preventing cancer remains unclear. OBJECTIVES: We prospectively examined the association between multivitamin use and risks of overall and site-specific cancer in a large, well-characterized cohort to ascertain potential preventive or harmful relationships. METHODS: We examined 489,640 participants ages 50-71 in the NIH-American Association of Retired Persons (AARP) Diet and Health Study who were enrolled from 1995 to 1998. We linked to 11 state cancer registries in order to identify incident cancers. Multivitamin use was assessed by a baseline questionnaire. Cox proportional hazards regression models of multivitamin use were used to estimate HRs and 95% CIs for cancer risks in men and women, adjusted for potential confounders, including age, BMI, smoking, physical activity, the Healthy Eating Index 2015 score, and use of single-vitamin/-mineral supplements. RESULTS: A slightly higher overall cancer risk was observed in men (but not women) who consumed 1 or more multivitamins daily compared to nonusers [HRs, 1.02 (95% CI: 1.01-1.04) and 1.03 (95% CI: 1.00-1.07), respectively; P-trend = 0.002]. The latter reflected higher risks for prostate cancer (HR, 1.04; 95% CI: 0.98-1.10; P-trend = 0.005), lung cancer (HR, 1.07; 95% CI: 0.96-1.20; P-trend = 0.003), and leukemia (HR, 1.26; 95% CI: 1.02-1.57; P-trend = 0.003). Taking more than 1 multivitamin daily was also strongly positively associated with the risk of oropharyngeal cancer in women (HR, 1.53, 95% CI: 1.04-2.24; P-trend < 0.0001). By contrast, daily multivitamin use was inversely associated with the colon cancer risk in both sexes (HR, 0.82; 95% CI: 0.73-0.93; P-trend = 0.0003). CONCLUSIONS: We found little evidence to support a cancer-preventive role for multivitamin use, with the exception of colon cancer, in both sexes in the NIH-AARP Diet and Health Study. In addition, slightly higher risks of overall, prostate, and lung cancer, as well as leukemia, were observed for greater multivitamin use in men, with a higher oropharyngeal cancer risk in women.

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality.

RATIONALE: Although there has been a long-standing interest in the human health effects of vitamin E, a comprehensive analysis of the association between circulating vitamin E and long-term mortality has not been conducted. OBJECTIVE: Determine whether serum α-tocopherol (the predominant form of vitamin E) is related to long-term overall and cause-specific mortality and elucidate the dose-response relationships with better quantification of the associations. METHODS AND RESULTS: We conducted a biochemical analysis of 29 092 participants in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) that originally tested vitamin E and ß-carotene supplementation. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and during a 30-year follow-up we identified 23 787 deaths, including deaths from cardiovascular disease (9867), cancer (7687), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2698). After adjusting for major risk factors, we found that men with higher serum α-tocopherol had significantly lower all-cause mortality (hazard ratios=0.83, 0.79, 0.75, and 0.78 for quintile 2 (Q2)-Q5 versus Q1, respectively; Ptrend<0.0001), and significantly decreased mortality from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, and other causes, with risk reductions from 17% to 47% for the highest versus lowest quintile. The α-tocopherol association with overall mortality was similar across subgroups of smoking intensity, years of smoking, alcohol consumption, trial supplementation, and duration of follow-up. The association was, however, significantly modified by baseline age and body mass index, with stronger inverse associations for younger men and men with a lower body mass index ( Pinteraction≤0.006). CONCLUSIONS: In this long-term prospective cohort study, higher baseline serum α-tocopherol biochemical status was associated with lower risk of overall mortality and mortality from all major causes. Our data support the long-term health benefits of higher serum α-tocopherol for overall and chronic disease mortality and should be replicated in other more diverse populations.

Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study.

OBJECTIVE: To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. DESIGN: We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis. RESULTS: Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10-5). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter. CONCLUSION: Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.

Vitamin D binding protein and risk of renal cell carcinoma in the prostate, lung, colorectal and ovarian cancer screening trial.

Our group has conducted two previous studies on the association between vitamin D binding protein (DBP) and renal cell carcinoma (RCC), the most common form of kidney cancer, finding strong inverse associations. We undertook the current analysis to replicate our findings in a different study population that included women and nonsmokers. We conducted a nested case-control study in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cases (n = 323) were matched 1:1 to controls on age (±1 year), race/ethnicity, date of blood collection (±30 days) and sex. We performed conditional logistic regression to estimate the odds ratios and 95% confidence intervals for the association between quartiles of circulating DBP and risk of RCC. We observed a statistically significant positive association between DBP and RCC that persisted after adjustment for history of diabetes, history of hypertension, family history of renal cancer, body mass index and smoking status (mv-adj Q4 vs. Q1 OR = 4.1, 95% CI = 2.2-7.8; p-trend <0.0001). These findings were similar when we restricted to cases with at least 2 years of follow-up and no major weight loss, suggesting that our findings are not due to reverse causality. In the present study, those with higher serum concentrations of DBP were at increased risk of RCC, in contrast to previously published findings. Further research is necessary to determine the true association between DBP and risk of RCC, and whether different DBP phenotypes may have different associations with risk of RCC.